This is a proposal to renew an ongoing, productive human laboratory research project directed toward identification and development of medications for treatment of cocaine dependence. The project has developed and will use an efficient and sensitive human laboratory screening procedure to assess the effects of potential pharmacotherapeutic approaches. The goal is to identify medications that modulate the abuse liability of cocaine or craving for cocaine. Within a residential laboratory volunteer experienced cocaine abusers will be challenged with intravenous cocaine. Challenge sessions consist of a series of ascending doses of i.v. cocaine at one-hr intervals, yielding a dose-effect characterization of the profile and time course of cocaine's subjective and physiological effects. Potential pharmacotherapies are evaluated by superimposing the cocaine challenge test procedure on a schedule of chronic ascending-dose administration (and then discontinuation) of the potential pharmacotherapy -- yielding a dose-effect characterization of the effects of the pharmacotherapy alone, and of its modulation of or interaction with the cocaine response. Medications that alter cocaine response may have potential as anti-cocaine pharmacotherapies, or may help identify mechanisms relevant to developing such pharmacotherapies. Assessment will be multidimensional, including subjective, behavioral, and physiological. Intensive electrocardiologic recordings will assess for potential cardiologic effects relevant to safety of the test medications, including disturbances of autonomic balance as indicated by heart rate variability indices. Potential pharmacotherapeutic approaches to be tested include: oral cocaine (testing the feasibility of an agonist-substitution approach to cocaine dependence pharmacotherapy); the neuroleptic and dopamine partial agonist (+)UH232; the serotonergic agent tryptophan; a dopamine D-1 antagonist; a blocker of cocaine binding at the dopamine transporter; the combination of phentermine and fenfluramine, which combines dopaminergic and serotonergic activities; and/or other promising agents that become available for human testing during the term of this project. These studies will provide valuable data concerning both the safety and the potential efficacy of the tested pharmacotherapies alone and in combination with cocaine. This may be an efficient procedure for identifying pharmacotherapies sufficiently promising to warrant outpatient therapeutic trials. By testing in the laboratory some pharmacotherapies that also receive outpatient clinical trial evaluation, this project will help to address the relative merits of human laboratory studies versus outpatient clinical trials as strategies for drug abuse medications development research.
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